In 1999, 360,076 cases of gonorrhea were reported in the United States
(1). Gonorrhea is a major cause of pelvic inflammatory disease, often leading to
ectopic pregnancy and infertility, and it can facilitate human immunodeficiency virus
(HIV) transmission (2). During the 1980s, resistance to penicillin and tetracycline
among gonococcal isolates became widespread; as a result, CDC recommended that
other antimicrobial agents be used to treat gonorrhea. This report
summarizes investigations of an increase in
fluoroquinolone-resistant Neisseria
gonorrhoeae in Hawaii and of a cluster of N.
gonorrhoeae infections with decreased susceptibility
to azithromycin in Missouri.

N. gonorrhoeae withfluoroquinolone-resistance, Hawaii

The susceptibility of N. gonorrhoeae to ciprofloxacin is used to
assess susceptibility to all equivalent fluoroquinolone antimicrobials. The Hawaii
Department of Health State Laboratory (HSL) routinely performs antimicrobial
susceptibility testing on all gonococcal isolates identified by culture. HSL also submits
gonococcal isolates from the Diamond Head Health Center STD and HIV Clinic in Honolulu,
Hawaii, to the Gonococcal Isolate Surveillance Project (GISP), a CDC-sponsored
sentinel surveillance system that monitors antimicrobial resistance of
N. gonorrhoeae. The 26 sexually transmitted disease (STD) clinics in the United States that participate in
GISP collect male urethral gonococcal cultures and submit them to one of five
regional GISP laboratories for antimicrobial susceptibility testing.

An increase in the number of ciprofloxacin-resistant (CipR)* gonococcal
isolates submitted by HSL to CDC for reference characterization in 1999
(3) prompted CDC and the Hawaii Department of Health (HDH) to initiate an investigation in September
1999. Military, public, and private laboratories were contacted to ascertain routine
gonorrhea testing methods (culture versus nonculture). In 1998, 507 gonorrhea cases
were reported to HDH. Of these, 256 (50%) were diagnosed by culture and
underwent antimicrobial susceptibility testing at HSL. Antimicrobial susceptibility testing
records of gonococcal isolates originating in Hawaii from HSL, GISP, and CDC were
reviewed to identify CipR gonococcal isolates and determine their prevalence in Hawaii.

From January 1990 through September 1999, 105 gonococcal isolates
were
identified that were CipR (n=48) or had intermediate resistance to ciprofloxacin
(CipI) (n=57). For CipR isolates, the median ciprofloxacin minimal inhibitory
concentration (MIC) was 2.0 µg/mL (range: 1.0--16.0
µg/mL). The percentage of gonococcal isolates
in Hawaii that were CipR increased from 1.4% (four of 290) in 1997 to 9.5% (22 of 231)
in 1999 (Figure 1).

Of the 105 patients with CipR/CipI gonorrhea, sex was known for 97;
medical records were available for 81. The median age was 30 years (range: 16--53 years),
and 68 (70%) were male. Of 79 with reported race/ethnicity, 42 (53%) were
Asians/Pacific Islanders, and 20 (25%) were white. The median number of reported sexual
partners during the preceding 30 days was one (range: 0--3). Five (9%) of 55 persons
identified themselves as homosexual or bisexual. Nine (12%) of 73 reported antimicrobial
use (fluoroquinolone use was reported by one patient) during the 30 days before
diagnosis of gonorrhea. Thirty (48%) of 62 denied foreign travel during the 30 days
before diagnosis or having a sex partner with a similar history; 72 (91%) of 79 were
treated with ceftriaxone or cefixime for their gonorrhea.

Of 75 CipR/CipI isolates, 48 (64%) were resistant to penicillin; 28 (37%)
were penicillinase-producing N. gonorrhoeae. In addition, 33 (44%) were resistant
to tetracycline; one had plasmid-mediated tetracycline resistance. Among isolates
tested for susceptibility to other antimicrobial agents, no evidence was found of
decreased susceptibility to ceftriaxone, cefixime, or azithromycin, or resistance to spectinomycin.

During March--December 1999, GISP identified a cluster of 12 men with
gonorrhea who had decreased susceptibility to azithromycin
(AziDS)§. The patients were seen
at the Kansas City, Missouri STD clinic. In February 2000, CDC, the Missouri
Department of Health and the Kansas City Health Department investigated this cluster.
Medical records of the 12 patients were reviewed. The median age was 33 years (range:
23--44 years), and 10 were black. Six reported sex with a commercial sex worker, and all
12 denied sexual contact with other men. Two were HIV infected. Two
reported antimicrobial use during the 30 days before diagnosis. All 12 were treated
with cefixime.

The median MIC for azithromycin was 2.0
µg/mL (range: 1.0--4.0
µg/mL). Preliminary laboratory data, including antimicrobial susceptibility results,
auxotype, serovar, and Lip subtype (4), suggest the gonococcal strains were identical among
the 12 patients. All isolates were susceptible to ceftriaxone, cefixime,
spectinomycin, ciprofloxacin, and penicillin. Eleven of the gonococcal isolates had
intermediate resistance to tetracycline (MIC=1.0
µg/mL); the remaining isolate was resistant
to tetracycline (MIC=2.0 µg/mL) but was within testing variability of the results for
the other 11.

Editorial Note:

Antimicrobial resistance is an ongoing challenge for
gonorrhea treatment and control. These investigations highlight an increased prevalence
of fluoroquinolone-resistant gonorrhea in Hawaii and the emergence in Kansas City
of the first reported cluster of patients with AziDS gonorrhea. These reports are
limited to describing data routinely documented in medical records. Interviews with
the patients and prospective data collection at STD clinics in both areas will
provide detailed information on risk factors (e.g., recent travel, recent antimicrobial use,
and contact with commercial sex workers).

CDC recommendations for gonorrhea therapy include use of either of
two fluoroquinolone antimicrobials (ciprofloxacin or ofloxacin) because they
are inexpensive, single-dose, oral medications
(5). Fluoroquinolones are used widely in
the United States to treat gonorrhea. Although infections with
fluoroquinolone-resistant N. gonorrhoeae are endemic in many Asian countries
(6), reports have documented only sporadic isolation of these strains in the United States
(1). Excluding Hawaii, 0.2% of GISP isolates in 1999 were resistant to fluoroquinolones
(1). Fluoroquinolone-resistant N.
gonorrhoeae were first reported in the continental United States in 1995
in eight patients in Washington and one in Colorado
(7).

HDH and CDC recommend clinicians in Hawaii no longer use
fluoroquinolone
antimicrobials to treat gonorrhea. Absence of foreign travel among 48% of
patients with CipR/CipI gonorrhea or their reported sex partners suggests CipR
N. gonorrhoeae are being spread endemically in Hawaii. Therefore, for patients
with gonorrhea in the United States, travel history, including sex partner travel
history, should be obtained. If patients or their sex partners are likely to have
acquired gonococcal infections in Hawaii, the Pacific Islands, or Asia, they should not be
treated with fluoroquinolone antimicrobials; instead, ceftriaxone or cefixime should be
used. For those unable to tolerate a cephalosporin, spectinomycin should be used.

AziDS gonococcal isolates rarely have been reported in the United States
or worldwide (8--10). Azithromycin is used widely to treat many
community-acquired infections in the United States. In addition, a 1 g dose of azithromycin is
recommended by CDC to treat Chlamydia
trachomatis infections (5). However, this dose
is inadequate to treat gonorrhea. Although a 2 g dose of azithromycin is approved
for gonorrhea therapy by the U.S. Food and Drug Administration, CDC does
not recommend routine treatment of gonorrhea infections with azithromycin because
of cost and gastrointestinal intolerance at this dose
(5).

N. gonorrhoeae must be grown in culture for antimicrobial susceptibility testing
to be performed. The increasingly widespread use of nonculture methods for
gonorrhea diagnosis is a major challenge to monitoring antimicrobial resistance in
N. gonorrhoeae. The changes in antimicrobial resistance patterns described in this
report were identified only because culture was used as the diagnostic testing method
in these sites and because susceptibilities were being measured through GISP
for Kansas City. HSL is one of the few state public health laboratories
performing antimicrobial susceptibility testing on all gonococcal isolates identified by culture.

Clinicians who suspect or identify a N.
gonorrhoeae infection treatment failure should submit a gonococcal culture specimen to the local health laboratory
for susceptibility testing. CDC requests reports of treatment failures or
resistant gonococcal isolates from clinicians or laboratories (National Center for HIV, STD
and TB Prevention, Division of STD Prevention, telephone [404] 639-8373).
CDC recommends that local health laboratories with the capacity to perform
antimicrobial susceptibility testing on N.
gonorrhoeae isolates routinely test for susceptibility
to antimicrobials used locally for gonorrhea treatment (e.g., a fluoroquinolone,
cefixime or ceftriaxone, azithromycin, and spectinomycin). Gonococcal isolates resistant
to these classes of antimicrobials can be forwarded to CDC's Neisseria
Reference Laboratory (telephone [404] 639-2134) for confirmation and further evaluation.

* Resistance to ciprofloxacin is defined by the National Committee on Clinical
Laboratory Standards as a minimal inhibitory concentration of
>1.0 µg/mL by agar dilution or
disk diffusion zone size of <27 mm.

 Intermediate resistance to ciprofloxacin is defined by National Committee on
Clinical Laboratory Standards as minimum inhibiting concentration=0.125--0.5
µg/mL by agar dilution or a disk diffusion zone size of 28--35 mm.

§ Decreased susceptibility to azithromycin was defined for this investigation as MIC of
>1.0 µg/mL. No National Committee on Clinical Laboratory
Standards criteria exist for decreased
susceptibility or resistance to azithromycin for
N. gonorrhoeae.

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